Patent EP-0114128-B1 (EP)
IPC: C07D417/14
Filed: 1984-01-06
Granted: 1989-03-22
Abstract: 1. Claims : For the contracting states : BE, SE, CH, DE, FR, GB, IT, LI, LU, NL Products of general formula (I) :  see diagramm : EP0114128,P43,F6  in which R represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from carboxy radicals, optionally salified or esterified ; amino, methylamino, dimethylamino and diethylamino radicals ; the phenyl radical optionally substituted by one or more radicals chosen from the following radicals : hydroxy, methyl, methoxy, chloro, bromo, fluoro ; fluoro, chloro, bromo or iodo radicals ; nitrile, CONH2 or CONH SO2 R" radicals in which R" represents an alkyl radical having from 1 to 4 carbon atoms ; a phenyl radical, an amino, methyl or dimethylamino radical ; a heterocyclic amino radical chosen from piperidino, morpholino piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; - a cycloalkyl radical having from 3 to 8 carbon atoms or a radical : see diagramm : EP0114128,P44,F1  salified or esterified, in which nc represents a whole number from 0 to 5, - one of the following radicals : acetyl, propionyl or benzoyl, carbamoyl, dimethylamino carbonyl, phenyl or benzyl optionally substituted by alkyl, alkoxy or halogen ; R1 represents a hydrogen atom, an alkyl, alkenyl, alkynyl or thioalkyl radical having a the most 12 carbon atoms, optionally substituted by one or more radicals chosen from azido or alkylthio radicals having from 1 to 4 carbon atoms or a phenylthio radical, optionally salified or esterified carboxy radicals, amino, methylamino, dimethylamino or diethylamino radicals, the phenyl radical, optionally substituted by one or more radicals chosen from hydroxy, halogeno, trifluoromethyl, amino, alkyl or alkoxy radicals having from 1 to 4 carbon atoms ; fluoro, chloro, bromo or iodo radicals, nitrile, CONH2 or CONH SO2 R" radicals in which R" represents an alkyl radical having from 1 to 4 carbon atoms, a phenyl radical, an amino, methyl or dimethylamino radical, a heterocyclic amino radical chosen from piperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; a heterocyclic aryl radical chosen from the following radicals : thienyl, furyl, pyrannyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl ; and the following radicals : acetoxy, propionyloxy, benzoyloxy, acetylamino, benzylcarbonyl, carbamoyloxy, methylaminocarbonyloxy or dimethylaminocarbonyloxy, acetyl, propionyl, and benzoyl, - a free, esterified or salified carboxy radical, - a phenyl radical optionally substituted by one of the following radicals : alkyl, trifluoromethyl, alkoxy, alkylthio, halogen, hydroxyl, amino or hydroxylakyl, a heterocyclic radical chosen from the following radicals : thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl optionally substituted by an alkyl, carboxy, carboxy alkyl, aminoalkyl or dialkylaminoalkyl radical, - an acetyl, propionyl, n-butyryl or benzoyl radical, optionally substituted by alkoxy or hydroxy, - a carbamoyl, methyl or dimethylcarbamoyl radical, - a azido radical. R2 represents a nitrogen-containing heterocycle optionally substituted by one or more of the radicals chosen from the group formed by the following radicals : nitro, carboxy, CF3 , nitrile, halogen, sulpho, alkylsulpho, (CH2 )n SO3 H, (CH2 )n NHSO3 H, (CH2 )n SO2 NH2 , (CH2 )n CO2 H, in which n represents a whole number from 1 to 4 and containing at least one acid hydrogen, X represents a CH radical or a nitrogen atom, the wavy lines indicate that the OR radical can exist in cis or trans form or in the form of a cis-trans mixture, the products of formula (I) being in racemic or optically active form, as well as the salts of the products of formula (I) withthe bases and acids. 1. Claims : For the contracting state AT Process for preparing the products of general formula (I) :  see diagramm : EP0114128,P48,F3  in which R represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from carboxy radicals, optionally salified or esterified ; amino, methylamino, dimethylamino and diethylamino radicals ; the phenyl radical optionally substituted by one or more radicals chosen from the following radicals : hydroxy, methyl, methoxy, chloro, bromo, fluoro ; fluoro, chloro, bromo or iodo radicals ; nitrile, CONH2 or CONH SO2 R" raidcals in which R" represents an alkyl radical having from 1 to 4 carbon atoms ; a phenyl radical ; an amino, methyl or dimethylamino radical ; a heterocyclic amino radical chosen from piperidino, morpholino piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; - a cycloalkyl radical having from 3 to 8 carbon atoms or a radical : see diagramm : EP0114128,P48,F1  salified or esterified, in which nc represents a whole number from 0 to 5, - one of the following radicals : acetyl, propionyl, or benzoyl, carbamoyl, dimethylamino carbonyl, phenyl or benzyl optionally substituted by alkyl, alkoxy or halogen ; R1 represents a hydrogen atom, an alkyl, alkenyl, alkynyl or thioalkyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from azido or alkylthio radicals having from 1 to 4 carbon atoms or a phenylthio radical, optionally salified or esterified carboxy radicals, amino, methylamino, dimethylamino or diethylamino radicals, the phenyl radical, optionally substituted by one or more radicals chosen from hydroxy, halogeno, trifluoromethyl, amino, alkyl or alkoxy radicals having from 1 to 4 carbon atoms ; fluoro, chloro, bromo or iodo radicals, nitrile, CONH2 or CONH SO2 R" which R" represents an alkyl radical having from 1 to 4 carbon atoms, a phenyl radical, an amino, methyl or dimethylamino radical, a heterocyclic amino radical chosen from piperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; a heterocyclic aryl radical chosen from the following radicals : thienyl, furyl, pyrannyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl ; and the following radicals : acetoxy, propionyloxy, benzoyloxy, acetylamino, benzylcarbonyl, carbamoyloxy, methylaminocarbonyloxy or dimethylaminocarbonyloxy, acetyl, propionyl, and benzoyl, - a free, esterified or salified carboxy radical, - a phenyl radical optionally substituted by one of the following radicals : alkyl, trifluoromethyl, alkoxy, alkylthio, halogen, hydroxyl, amino or hydroxyalkyl, a heterocyclic radical chosen from the following radicals : thienyl, furyl, pyrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl optionally substituted by an alkyl, carboxy, carboxy alkyl, aminoalkyl or dialkylaminoalkyl radical, - an acetyl, propionyl, n-butyryl or benzoyl radical, optionally substituted by alkoxy or hydroxy, - a carbamoyl, methyl or dimethylcarbamoyl radical, - an azido radical. R2 represents a nitrogen-containing heterocycle optionally substituted by one or more of the radicals chosen from the group formed by the following radicals : nitro, carboxy, CF3 , nitrile, halogen, sulpho, alkylsulpho, (CH2 )n SO3 H, (CH2 )n NHSO3 H, (CH2 )n SO2 NH2 , (CH2 )n CO2 H, in which n represents a whole number from 1 to 4 and containing at least one acid hydrogen, X represents a CH radical or a nitrogen atom, the wavy lines indicate that the OR radical can exist in cis or trans form or in the form of a cis-trans mixture, the products of formula (I) being in racemic or optically active form, as well as the salts of the products of formula (I) with the acids and bases, characterized in that a product of formula (II) :  see diagramm : EP0114128,P49,F1  cis or trans, racemic or optically active, in which formula either R1 p represents R1 , R1 having the previously indicated significance, or R1 p represents the substituent R1 in which the reactive functions are protected and either R2 p represents R2 , R2 having the previously indicated significance, or R2 p represents the substituent R2 in which the reactive functions are protected, is treated with a product of formula (III) :  see diagramm : EP0114128,P49,F3  syn or anti, in which Rb represents a hydrogen atom or a protector group of the amino radical and Rp represents a protector group of the hydroxyl radical or Rp represents R, R having the significance indicated in claim 1, or Rp represents a radical R in which the reactive functions are protected, so as to obtain a product of formula (IV) :  see diagramm : EP0114128,P49,F5 syn or anti, racemic or optically active, in which Rp, R1 p, R2 p and Rb have the previous significance, which product is submitted, if necessary and if desired, to any one of the following reactions, in any order : a) cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the protector group or groups which can be represented by Rb and Rp or can be contained in Rp, R1 p and R2 p ; b) esterification or salification of the carboxy or sulpho radicals which can be contained in the radicals Rp, R1 p and R2 p ; c) salification by an acid of the amino radical or radicals ; d) resolution of the molecule so as to obtain an optically active product.